HOST CELL INTERACTIONS BY PATHOGENIC BORRELIAE

致病性疏螺旋体与宿主细胞的相互作用

• 批准号: 6130396
• 负责人: JOHN M LEONG
• 金额: $ 31.2万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6130396
• 关键词: Borrelia; Lyme disease; bacteria infection mechanism; bacterial proteins; biological signal transduction; blood circulation; blood toxicology; cell type; epitope mapping; erythrocytes; gene expression; glycoproteins; host organism interaction; human tissue; integrins; laboratory mouse; leukocyte adhesion molecules; mucopolysaccharides; pathologic process; platelet activation; protein binding; protein structure function; proteoglycan; thrombocytopenia; virulence

Borrelia burgdorferi is the causative agent of Lyme disease, and B. hermsii and B. turicatae are causative agents of tick-borne relapsing fever. Pathogen-host cell interactions are thought to be critical determinants of the site and severity of infection, and we have focused on Borrehae recognition of two classes of host cell molecules: (1) glycosaminoglycans (GAGs); and (2) integrins and their associated proteins. For B. burgdorferi, we found that differences in GAG recognition were associated with differences in host cell type-specific binding, and identified a surface protein, Bgp, that may be the major B. burgdorferi GAG receptor. This bacterium also recognizes the activation- dependent platelet integrin alphaIIbbeta3, and thereby selectively binds to activated (vs. resting) platelets. This integrin-binding activity is predicted to target the Lyme disease spirochete to the vessel wall at sites of platelet adherence, and could explain a salient feature of Lyme disease: vascular pathology of the arterial circulation. In our studies of relapsing fever spirochetes. high-level GAG- binding correlated with high-level growth in the bloodstream and a variable major protein. VspB, promoted attachment to GAGS. Additionally, to contrast to B. burgdorferi, B. hermsii bound and activated resting platelets. This contact-dependent platelet activation activity was apparently mediated by the integrin- associated platelet signaling molecule CD9. Relapsing fever spirochetes have also been shown to bind to erythrocytes, and we speculate that attachment of relapsing fever spirochetes to circulating blood cells such as platelets and erythrocytes could promote the retention and high level growth of the bacteria in the blood. Interaction of spirochetes with these two cell types could also contribute to two common manifestations of relapsing fever: anemia and thrombocytopenia. Thus, we have formulated working models for the role of host cell binding in colonization and disease expression by pathogenic Borrehae. To test predictions of these models, the following questions will be addressed: (1) does reducing the spirochete- platelet interactions affect colonization of the vessel wall and heart in Lyme disease or thrombocytopenia in relapsing fever? (2) does CD9 play a role in platelet activation by B. hermsii? (3) does the GAG-binding activity of the relapsing fever spirochete influence cell attachment and growth in the bloodstream of infected animals? (4) does Bgp play a predominant role in GAG binding by B. burgdorferi? The proposed experiments may uncover both potential therapeutic strategies for combating Borreliae infections as well as general principles that govern tissue-specific infection by bacterial pathogens.

伯氏疏螺旋体是莱姆病的病原体，而赫氏疏螺旋体和图里卡特氏疏螺旋体是硬虱传播的复发热的病原体。病原体-宿主细胞的相互作用被认为是感染部位和严重程度的关键决定因素，我们重点介绍了Borrehae对两类宿主细胞分子的识别：(1)糖胺聚糖(GAG)；(2)整合素及其相关蛋白。对于Burgdorferi，我们发现GAG识别的差异与宿主细胞类型特异性结合的差异有关，并确定了一种表面蛋白BGP，它可能是Burgdorferi Gag的主要受体。该细菌还识别依赖于激活的血小板整合素AlphaIIbbeta3，从而选择性地与激活的(与静止的)血小板结合。这种整合素结合活性被预测为将莱姆病螺旋体定位于血小板粘连部位的血管壁，并可以解释莱姆病的一个显著特征：动脉循环的血管病理。在我们对回归热螺旋体的研究中。高水平的Gag结合与血液中的高水平生长和一种可变的主要蛋白质相关。VspB，促进对恶作剧的依恋。此外，与伯氏杆菌不同的是，赫氏杆菌结合并激活了静息的血小板。这种接触性的血小板激活活性显然是由整合素相关的血小板信号分子CD9介导的。回归热螺旋体也被证明与红细胞结合，我们推测回归热螺旋体附着在循环血细胞上，如血小板和红细胞，可以促进细菌在血液中的滞留和高水平生长。螺旋体与这两种细胞类型的相互作用也可能导致复发发热的两种常见表现：贫血和血小板减少。因此，我们已经建立了宿主细胞结合在致病Borrehae的定植和疾病表达中所起作用的工作模型。为了验证这些模型的预测，将解决以下问题：(1)减少螺旋体与血小板的相互作用是否会影响莱姆病患者的血管壁和心脏的定植，或者复发发热时的血小板减少？(2)CD9在赫氏杆菌激活血小板中是否起作用？(3)复发发热螺旋体的Gag结合活性是否影响感染动物血液中的细胞附着和生长？(4)BGP在B.burgdorferi的Gag结合中是否起主导作用？拟议的实验可能既揭示了对抗疏螺旋体感染的潜在治疗策略，也揭示了管理由细菌病原体引起的组织特异性感染的一般原则。